Assessment of the Endocrine-Disrupting Effects Of

Food and Chemical Toxicology 133 (2019) 110759 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Assessment of the endocrine-disrupting effects of organophosphorus T pesticide triazophos and its metabolites on endocrine hormones biosynthesis, transport and receptor binding in silico ⁎ Fang-Wei Yanga, Yi-Xuan Lia, Fa-Zheng Rena,b, Jie Luoa,c, Guo-Fang Panga,d, a Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China b Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, Beijing Laboratory of Food Quality and Safety, China Agricultural University, Beijing, 100083, China c College of Food Science and Technology, Hunan Agricultural University, Changsha, 410114, China d Chinese Academy of Inspection and Quarantine, Beijing, 100176, China ARTICLE INFO ABSTRACT Keywords: Triazophos (TAP) was a widely used organophosphorus insecticide in developing countries. TAP could produce Triazophos specific metabolites triazophos-oxon (TAPO) and 1-phenyl-3-hydroxy-1,2,4-triazole (PHT) and non-specific Metabolites metabolites diethylthiophosphate (DETP) and diethylphosphate (DEP). The objective of this study involved Endocrine disruption computational approaches to discover potential mechanisms of molecular interaction of TAP and its major Hormones metabolites with endocrine hormone-related proteins using molecular docking in silico. We found that TAP, Molecular docking TAPO and DEP showed high binding affinity with more proteins and enzymes than PHT and DETP. TAPmight interfere with the endocrine function of the adrenal gland, and TAP might also bind strongly with glucocorticoid receptors and thyroid hormone receptors. TAPO might disrupt the normal binding of androgen receptor, es- trogen receptor, progesterone receptor and adrenergic receptor to their natural hormone ligands. DEP might affect biosynthesis of steroid hormones and thyroid hormones. Meanwhile, DEP might disrupt the bindingand transport of thyroid hormones in the blood and the normal binding of thyroid hormones to their receptors. These results suggested that TAP and DEP might have endocrine disrupting activities and were potential endocrine disrupting chemicals. Our results provided further reference for the comprehensive evaluation of toxicity of organophosphorus chemicals and their metabolites. 1. Introduction represented a risk to human health as well as the ecological system due to its high chemical and photochemical stability (http://sitem.herts.ac. 1.1. Chemical characteristics, residues and toxicity of triazophos uk/aeru/iupac/Reports/653.htm). According to the classification standard of World Health Organization (WHO), TAP was a Class Ib toxic Triazophos/Triazofos/Hostathion/Phentriazophos (O,O-diethyl-O- organophosphorus insecticide (WHO, 2010). The neurotoxicity, hepa- (1-phenyl-1H-1,2,4-triazol-3-yl) phosphorothioate, CAS Registry No. totoxicity, nephrotoxicity, reproductive toxicity and genotoxicity of 24017-47-8, chemical formula C12H16N3O3PS, molar mass TAP attracted considerable public attention over the last decade. It was 313.31 g mol−1, log Kow 3.55, abbreviated as TAP) was an efficient and reported that TAP had fairly high lethal toxicity to aquatic creatures broad-spectrum organophosphorus pesticide (OP) used as insecticide, and posed a threat to the health of aquatic ecosystems (Wang et al., nematicide and acaricide, which was widely used in Asian countries, 2010; Wu et al., 2018; Zhang et al., 2018a,b,c). Recent research also such as China, India, Pakistan, to protect various crops like cotton, rice, revealed that TAP induced oxidative stress and histomorphological wheat, tea, fruits, oil seeds and vegetables (Bhandari et al., 2019; Chen changes in rats (Jain et al., 2011, 2013; Sharma and Sangha, 2014; et al., 2009; Duan et al., 2016; Fang et al., 2015; Hong et al., 2019; Sharma et al., 2015a, 2015b). Zhang et al. (2011) found that TAP Kumari and John, 2019). However, the widespread application of TAP chronic dietary intake represented a significant risk to the elderly ⁎ Corresponding author. Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University. No. 17 Qinghua East Road, Haidian District, Beijing, 100083, China. E-mail address: [email protected] (G.-F. Pang). https://doi.org/10.1016/j.fct.2019.110759 Received 18 June 2019; Received in revised form 31 July 2019; Accepted 12 August 2019 Available online 14 August 2019 0278-6915/ © 2019 Elsevier Ltd. All rights reserved. F.-W. Yang, et al. Food and Chemical Toxicology 133 (2019) 110759 persons and an acute nutritional intake risk of TAP residues in apple, 1.4. Screening, identification and risk assessment of endocrine disrupting cabbage, rice and wheat meal reached an unacceptable range in China. chemicals in silico Therefore, the wide application of TAP raised concerns on the environmental pollution and the potential risk to human health. Exogenous chemicals, exposed through the environmental and dietary pathways, had potential endocrine disruption effects that harm human health and the ecosystem (Giulivo et al., 2016; He et al., 2015; 1.2. Major degradation metabolites of TAP Mimoto et al., 2017; Pande et al., 2019). Endocrine disrupting chemicals (EDCs) caused a variety of diseases, such as reproductive diseases, After reaching the liver, TAP would produce specific metabolites metabolic diseases and even cancers, by interfering with the endocrine triazophos-oxon (TAPO), 1-phenyl-3-hydroxy-1,2,4-triazole (PHT), and system (The Lancet Diabetes & Endocrinology, 2019). If all the potential non-specific metabolites diethylthiophosphate (DETP) and diethylpho- EDCs in the environment and foods were to be screened via traditional sphate (DEP) under the action of a series of metabolic detoxification in vitro and in vivo methods, this would constitute an unbearable fi- enzymes (Bock and Their, 1976; Schwalbe-Fehl and Schmidt, 1986; nancial burden, would conflict with the “3R” principles of animal-use Wang et al., 2015). Briefly, TAP desulfurized under the action of ethics, and the work would stretch over many years, making it difficult CYP450 enzymes to produce triazophos-oxon (TAPO). Because the in- to meet the needs of toxicity and ecological risk assessment for EDCs hibition of acetylcholinesterase by TAPO was stronger, this process was (Burgdorf et al., 2019; Chen et al., 2018). In recent years, with the rapid actually a “metabolic increased toxification” process, but TAPO was development of computer technology and three-dimensional structure more conducive to the subsequent hydrolysis of paraoxonase 1, and analysis methods of proteins, molecular docking technology has been TAPO was degraded into PHT and DEP. TAP could also be directly gradually applied to toxicological evaluation field, and computational decomposed into PHT and DETP under the action of glutathione and toxicology research was increasing, especially the study of EDCs glutathione S-transferase, and then DETP could be further desulfurized (Browne et al., 2018; Selvaraj et al., 2018; Sun et al., 2019). Compu- into DEP. It was worth noting that DETP and DEP were non-specific tational toxicology has been recommended as the screening and pre- metabolites of many OPs, such as TAP, chlorpyrifos, diazinon, para- dicting method by the Organization for Economic Co-operation and thion, and phorate. More importantly, both DETP and DEP had high Development (OECD) (OECD, 2018), the US Environmental Protection bioavailability, and the molar mass of human exposure to DETP and Agency (EPA) (Browne et al., 2017), and others. Meanwhile, the Nobel DEP was higher than that of OPs (Forsberg et al., 2011; Sudakin and Prize in Chemistry 2013 was awarded to Martin Karplus, Michael Le- Stone, 2011; Timchalk et al., 2007; Zhang et al., 2008). In fact, ap- vitt, and Arieh Warshel for developing the multiscale models of com- proximately 75% of the commonly used OPs could be metabolized and plex chemical systems (Karplus et al., 2013), which demonstrated that degraded into six dialkyl phosphates (DAPs) in vivo and in the en- in this era of exceptional computational power, in silico analyses could vironment, namely diethyldithiophosphate (DEDTP), DETP, DEP, di- be as important as those conducted in vitro, and computer molecular methyldithiophosphate (DMDTP), dimethylthiophosphate (DMTP), and simulation methods have made significant contributions to the devel- dimethylphosphate (DMP) (Shomar et al., 2014; Ueyama et al., 2015; opment of life sciences and drug researches. Molecular docking pro- Yusa et al., 2015). The concentrations of DAPs in human urine were vided another reasonable method for the evaluation of EDCs, especially often used as the biomarkers for the exposure of OPs to assess the for some compounds with missing experimental data, the application of correlation between OPs exposure and diseases (Bernieri et al., 2019; molecular docking to explore the roles of EDCs and putative targets can Omoike et al., 2015; Panuwet et al., 2018; Shrestha et al., 2018; Wang supplement limited experimental data and improve the overall toxicity et al., 2017a,b). Interestingly, some organophosphorus flame retardants assessment of EDCs (Chen et al., 2018; Vuorinen et al., 2015; Yuriev and plasticizers could also be degraded and metabolized

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